1. Technical Field
This invention relates to compounds which are active against the serotonin 5-HT2B receptor. They may be used to treat diseases characterized by dysfunctional or overly active 5-HT2B receptors.
2. Background Information
The serotonin 5-HT2B receptor was first characterized as the serotonogenic GPCR that controlled contraction in the rat stomach fundus (Clineschmidt, et al., 1985, J. Pharmacol. Exp. Ther., 235, 696). 5-HT2B has since been detected in human tissues including adipose tissue, central nervous system (CNS), heart, intestine, liver, lung, ovary, pancreas, prostate, salivary gland, skeletal muscle, spleen, testis, thymus, thyroid, trachea, uterus, and vasculature (Kursar et al., 1994, Mol. Pharmacol., 46, 227; Sanden et al., 2000, Neurochem Int., 36, 427-435; Borman et al., 2002 Br. J. Pharmacol., 135, 1144; Schmuck et al., 1994, FEBS Lett., 342, 85). Modulators of 5-HT2B, which include antagonists, partial antagonists, inverse agonists, and 5-HT2B desensitizers, may be used as treatments for disorders in these tissues in which activation of 5-HT2B has a direct or indirect role.
Control of serotonin (5-HT) levels and signaling is used to treat disorders of the central nervous system. These diseases include alcoholism and other addiction disorders, anxiety, bipolar disorder, concentration and memory disorders, depression, eating disorders, obsessive compulsive disorder, panic disorders, prostate hyperplasia, schizophrenia, sexual dysfunction, sleep disorders, and social phobia. Antagonists of 5-HT2B may have a role in treating these diseases of the central nervous system by mitigating effects of 5-HT.
A selective antagonist of 5-HT2B increases wakefulness and motor activity in rats (Kantor et al., 2004, Br. J. Pharmacol., 132, 1332). Thus 5-HT2B antagonists may treat sleep disorders such as narcolepsy, or be used to treat fatigue, lethargy, or poor concentration.
Modulation of 5-HT2B may control overeating. While the selective 5-HT2B agonist BW723C86 stimulates hyperphagia in rats, the 5-HT2B/2C antagonist SB206553 blocks the hyperphagic effect of BW723C86 (Kennett, 1997, Neuropharmacology, 36, 233). 5-HT also regulates both intestinal contraction and intestinal motility via regulation of proliferation of the interstitial cells of cajal (ICC). Antagonists of 5-HT2B block both the contractile response (Borman et al., 2002, Br. J. Pharmacol., 135, 1144) and the proliferation of ICC that stimulate motility (Wouters et al., 2007, Gastroenterology, 133, 897). Therefore, 5-HT2B modulators may be used to treat gastric motility disorders such as irritable bowel syndrome.
5-HT has a role in vascular contraction and relaxation, and can impact vascular and function, growth, and morphology. Pulmonary arterial hypertension (PAH) is associated with abnormal vascular proliferation in the lung. PAH has an increased risk in patients exposed to a selective 5-HT2B agonist generated from the metabolism from dexfenfluramine. While wild-type mice develop symptoms of PAH under hypoxic conditions, 5-HT2B receptor knock-out mice do not. Moreover, the selective 5-HT2B antagonist RS127445 prevented the development of PAH symptoms in wild-type mice (Launay et al., 2002, Nature Med., 1129; Esteve et al., 2007, Cell Biochem. Biophys., 47, 33). This suggests modulation of 5-HT2B may be a treatment for PAH. Indeed, the selective 5-HT2B antagonist PRX-08066 has demonstrated primary efficacy in Phase IIa clinical trials for PAH in man (EPIX Pharmaceuticals Inc. Media Release, http://www.epixpharma.com).
Renal function is also dependent on the proper regulation of blood flow. The selective 5-HT2B agonist BW723C86 stimulates both an increase in renal nerve activity and decrease in renal blood pressure in rats. These effects are blocked by treatment with the 5-HT2B/2C antagonist SB204741 but not with a selective 5-HT2C antagonist (Knowles et al., 2000, Br. J. Pharmacol., 129, 177). Therefore, modulation of 5-HT2B activity may treat diseases associated with renal hypotension such as acute renal failure.
Migraine headaches are associated with dysfunction of the meningeal blood flow and are associated with elevated 5-HT levels. Many treatments for migraine demonstrate affinity for multiple 5-HT receptors, including significant modulation of 5-HT2B. Activation of 5-HT2B releases NO that is necessary for the genesis of migraine (Fozard et al., 1995, Arch. Int. Pharmacodyn. Ther., 329, 111; Schmuck et al., 1996, Eur. J. Neurosci., 8, 959). In a guinea pig model of migraine, the selective 5-HT2B antagonist LY202146 blocks mCPP induced dural plasma protein extravasation (Johnson et al., 2003, Cephalagia, 23, 117). In addition, the prophylactic migraine treatment dihydroergotamine modulates 5-HT2B activity by agonist-mediated desensitization via the metabolite 8′-hydroxy-dihydroergotamine (Schaerlinger et al., 2003, 140, 277).
Therefore, modulation of 5-HT2B may be a prophylactic treatment for migraine. Antagonism of 5-HT2B may additionally be used to treat hypertension. Rats treated with either deoxycorticosterone aceate-salt or Nω-nitro-L-arginine become hypertensive. Treatment of these hypertensive rats with the selective 5-HT2B antagonist LY272015 significantly reduces blood pressure. Moreover, the 5-HT2B protein levels are 2 to 3 fold higher in hypertensive rats than in the sham normotensive rats (Watts et al., 1999, Am. J. Physio. Hear Circ. Physiol., 276, H944; Banes et al., 2002, Hypertension, 39, 394; Russell et al., 2002, J. Pharmacol. Exp. Ther., 303, 179).
The phenotype of 5-HT2B receptor knock-out mice demonstrates the importance of this receptor for heart development. Surviving mice possess underdeveloped hearts resulting from impaired myocyte proliferation (Nebigil, et al., 2001, Circulation, 103, 2973). Conversely, 5-HT2B over expression in mice leads to cardiac hypertrophy (Nebigil, et al., 2003, Circulation, 107 (25), 3223). The selective antagonists of 5-HT2B SB206553 and SB215505 prevent isoproterenol induced cardiac hypertrophy (Jaffré et al., 2004, Circulation, 110, 969) Additionally, SB215505 was efficacious in a rat aortic banding model of cardiomyopathy (Liang et al., 2006, Cardio. Res., 72, 303). More recently, genomics data from a model of tachypacing-induced decompensatory heart failure in dogs showed an upregulation of 5-HT2B mRNA (Ojaimi et al., 2007, Physiol. Genomics 29, 76). An upregulation of 5-HT2B mRNA has also been reported in humans with cardiomyopathies (Oxford et al., 2005, USPTO Application 20050176791). Therefore, modulation of 5-HT2B may treat disorders associated with cardiac hypertrophy such as congestive heart failure.
While compounds of this invention have not been exemplified in the chemical and patent literature, [4-(1H-benzimidazol-2-yl)-piperidin-1-yl]-biphenyl-4-yl-methanone is available for purchase from commercial vendors.